This is a heterogeneous group of autosomal recessive disorders with a prevalence of about 1 in 70,000 of the population. It is characterized by hypersensitivity to UV light and a high incidence of UV-induced skin cancers. Clinical onset is before the age of 18 months in 50 %. Freckle-like skin lesions with erythema develop in sun-exposed skin in the first few years of life, and there may be extreme sunlight sensitivity. Macules of increased pigmentation develop on the skin and mucous membranes, and achromic areas may also occur. Subsequently, there is an atrophic and telangiectatic stage in which the skin becomes dry and scaly, with atrophy and spotted dyschromia.
Hyperkeratotic plaques, keratomas, keratoacanthomas, fibromas, angiomyomas, cutaneous horns, and other benign Tumours ensue, and there may be facial ulcerations. Multiple malignant basal and squamous cell carcinomas and malignant melanoma develop in sun-exposed areas; the risk for malignancy is up to 2,000-fold increase above normal. The median age at onset for skin cancer in XP has been estimated to be 8 years, compared with 60 years in the general population. Squamous cell carcinomas, sarcomas, melanomas, and epitheliomas may develop in the eyes and mucous membranes, and squamous cell carcinomas of the tongue and oropharynx may occur, with a relative risk of 10,000 times normal. Other malignant Tumours may develop, including neurinomas, sarcomas, and adenocarcinomas. It has been suggested that there is also a 10–20-fold increased incidence of internal neoplasms, such as lung, uterine, brain, breast, or testicular Tumours in XP. Actinic damage to the eyes may cause keratitis and conjunctivitis, which can lead to symblepharon and neoplasia, particularly at the corneoscleral junction. Entropion and ectropion may occur. Death results from disseminated Tumours, usually by the second or third decade (Giannelli and Pawsey 1976; Kraemer and Slor 1985).
De Sanctis–Cacchione syndrome emphasized neurological involvement in a subgroup of XP patients. Neurological complications are variable and include progressive mental deficiency, microcephaly, ataxia, choreoathetosis, spasticity, sensorineural deafness, and lower motor neuron and cranial nerve damage. Onset of these neurological abnormalities may be in infancy or later in childhood and may be mild or severe. They develop in about 18 % of cases of XP (Kraemer and Slor 1985). They can occur in any subgroup of XP but do so most commonly in complementation group D (XPD). Loss or absence of neurons may be demonstrated in the cerebrum or cerebellum at autopsy in these cases. The karyotype is normal, but there is hypersensitivity to chromosomal damage after exposure to UV light.
Different subgroups (complementation groups) of XP are described, each with a different type of mutation reducing the capacity for excision repair of UV-induced DNA damage (Giannelli 1986). These subgroups are associated with different clinical severity. Complementation group A (XPA) includes cases of all degrees of clinical severity, with and without neurological complications; group C (XPC) is the most commonly described, and most are neurologically normal. Cockayne syndrome with XP has been described in single cases (Neilan et al. 2008). The molecular bases for these conditions have been delineated and are due to various defects in solar-induced DNA damage. These defects comprise lack of a functional helicase, endonuclease, or lesion-recognizing protein involved in the initial steps of nucleotide excision repair. Different enzyme defects are found in the different complementation groups. They include proteins involved in recognition of photoproducts (XPE), and of other DNA defects such as pyrimidine dimers (XPA), DNA helicases (XPB, XPD), and endonucleases that perform two incisions (XPG), and single-strand-binding proteins (XPC) (Boulikas 1996; Chu and Mayne 1996). Prenatal diagnosis by chorionic villus sampling is becoming available in those families in which the mutation can be defined at the DNA level.
Mutations in eight genes may cause XP. The genes for group A and group C xeroderma pigmentosum (XPA and XPC) are involved solely in nucleotide excision repair, whereas the XPB and XPD proteins are both components of transcription factor TFIIH, which is involved in nucleotide excision repair, in basal transcription and in activated transcription (Lehmann 2003). All bona fide patients with XPE have a mutation in the DDB2 gene that encodes the smaller subunit of the heterodimeric damaged DNA-binding protein. XP group F (XPF) is caused by mutations in the ERCC4 gene and group G (XPG) by mutations in ERCC5.
XP variant (XP-V) is indistinguishable from XP clinically, except the neurological features do not develop. Unlike other XP cells belonging to XPA to XPG, XP-V cells have normal nucleotide excision repair processes but have defective replication of UV-damaged DNA. This form of XP is caused by mutations in the DNA polymerase eta gene (POLH) (Masutani et al. 1999). Suggestions of an increased risk of lung cancer in heterozygote carriers (for all relatives: relative risk, 1.93) (Swift and Chase 1979) have prompted association studies of XP gene variants and lung cancer risk with mixed results (Marin et al. 2004; Benhamou and Sarasin 2005).
Treatment is by protection from sunlight and careful surveillance, with early excision of Tumours. Avoidance of UV light should be instigated in childhood when the apparent health of young children makes this difficult. The use of an UV light meter can be helpful. It is interesting that spontaneous regression of malignant melanoma has been described to occur in XP, although the mechanism for this is not understood (Lynch et al. 1978).
Information for patients and their families is available from the xeroderma pigmentosum society.
Prenatal diagnosis of XP has been accomplished by demonstrating abnormal levels of DNA repair capacity on measurement of unscheduled DNA synthesis in UV-irradiated fetal amniocytes (Aras et al. 1985) or by mutation analysis.
A separate disorder of increased UVA sensitivity has been described, in which there is an autosomal dominant predisposition to the development of cutaneous pigmented keratoses in sun-exposed skin associated with the development of carcinoma of the uterus and other internal malignancies (clinically more apparent in females) (Atherton et al. 1989). Fibroblasts from affected individuals demonstrated an increased frequency of single-strand breaks in DNA following exposure to long-wave UVA.